Certain 5-acyl-2-(1H)-pyridinones useful in treating cardiac failure

ABSTRACT

Novel 5-acyl-2-(1H)-pyridinones and their use as cardiotonic agents. Typical of the compounds is 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile which is prepared by condensing anionic cyano acetamide with 3-[(dimethylamino)methylenyl]-2,4-pentanedione in an inert organic solvent.

This is a continuation of application Ser. No. 121,543, filed Nov. 17,1987; Pat. No. 4,853,385 which is a divisional of application Ser. No.867,825, filed May 27, 1986 now U.S. Pat. No. 4,731,371; which is adivisional of U.S. Ser. No. 594,767, filed Mar. 29, 1984, now abandoned;which is a continuation-in-part of U.S. Ser. No. 490,081, filed Apr. 29,1983, now U.S. Pat. No. 4,568,751.

This invention relates to 5-acyl-2-(1H)-pyridinones and to their use ascardiotonic agents.

More specifically, this invention relates to pharmaceutically active5-acyl-2-(1H)-pyridinones of the formula ##STR1## and thepharmaceutically acceptable salts thereof, wherein R₃ is H, --C≡N, NH₂,CONH₂ and COOR with

R being hydrogen or lower alkyl,

R₄ is hydrogen or lower alkyl,

R₅ is phenyl, X-substituted phenyl, pyridyl, thienyl, furyl, pyrrolyland OR wherein R is hydroxy or lower alkoxy, and X is lower alkyl, loweralkoxy, lower alkyl thio, halogen, nitro, lower alkanoyl, alkoxycarbonyl, carboxy, cyano, NH₂, CONH₂, amidino, imidazol-2-yl, and CF₃,and

R₆ is hydrogen, methyl, ethyl or R₅. These compounds are useful ascardiotonics in the treatment of cardiac failure and other conditionsrequiring strengthening of heart action with a cardiotonic agent.

As used herein, the term "alkyl" includes straight, branched-chain orcyclized hydrocarbyl radicals. The term "X-substituted phenyl" includethose substituents, preferably located in the para position but includesthe ortho and meta substituted compounds. The term "lower" when used tomodify alkyl, alkoxy, alkylthio embrace those radicals having one to sixcarbon atoms. Inclusive of other "x" radicals are alkoxycarbonyl (--COOlower, alkyl), lower alkanoyl (-CO-lower alkyl), amidino ##STR2##imidazol-2-yl ##STR3## and halogeno preferably includes chloro and bromobut is embrasive of all members. The term "pyridyl" includes 2-, 3-, and4-pyridyl, "furanyl" include 2- and 3-furanyl, "thienyl" includes 2- and3-thienyl, and "pyrryl" includes 2- and 3-(1H)-pyrryl.

The compounds of formula I are useful both in the free base form and inthe form of acid addition salts with both forms being within the purviewof this invention. The acid addition salts are simply a more convenientform for use and, in practice, use of the salt amounts to use of thefree base. The acids which can be used include those which produce, whencombined with the free base, pharmaceutically acceptable salts, that issalts whose anions are relatively inocuous to the animal organism inpharmaceutical doses of the salts. In practice, it is convenient to formsulfate, phosphate, methansulfate or laetate salts. Others are thosederived from mineral acids (e.g., hydrochloric), and organic acids suchas acetic acid, citric acid, tartaric acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like. The acidsalts are prepared by standard techniques such as by dissolving the freebase in aqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating by evaporating thesolution, or by reacting the free base and in an organic solvent inwhich case the salt separates directly or can be obtained byconcentration of the solution.

In general, the compounds of this invention are prepared by standardtechniques analogously known in the art. A preferred synthesis forpreparing the compounds of this invention conveniently involves thereaction of an appropriate 1-R₅ -3-R₆ -2-(1-dimethylamino-1-R₄-methylidenyl)-1,3-propanedione (II) with an appropriately R₃substituted acetoacetamide aCcording to standard Michael additionreaction conditions. Preferably, the substituted acetamide is reactedwith sodium hydride, under argon in an inert organic solvent, (e.g.,tetrahydrofuran) to form an anion which is then condensed with thediketone (II) by heating the reactants together in an inert organicsolvent, preferably tetrahydrofuran and the like. Preferably, thetemperature of the reaction is about 50° C. although the reactionproceeds well at temperatures between room temperature and 100° C.Heating is effected over a period of several hours although it ispreferred to allow the reaction to proceed overnight. When R₅ and R₆ arenot the same a mixture of products are obtained which are separatedquite nicely by flash chromatography wherein the reaction productmixture is admixed with 60 -200 mesh silica gel and the column is elutedwith an appropriate solvent system (e.g., 35% ethylacetate--65%methylene chloride). The fractions of eluate are monitored by thin layerchromatography.

The foregoing reaction is depicted as follows:

Reaction Scheme A ##STR4## wherein R₄, R₅ and R₆ are as previouslydefined, R₃ "is cyano, --CO₂ H, lower alkyl or NH₂ ; R₃ ' is cyano,--CO₂ H, lower alkyl or --N═CH phenyl.

The 1-R₅ -3R₆ -2-[(1-dimethylamino)alkylidenyl]-1,3-propanediones arereadily preparated by condensing the appropriate R₅, R₆-1,3-propandiones with the appropriately R₄ substitutedN,N-dialkylamino-dialkoxy methane (e.g., dimethylformamide acetalsaccording to standard condensation reaction conditions such as, forexample, contacting equimolar quantities of the reactants together,optionally in an inert organic solvent and stirring the mixture for 1-12hours at about room temperature. This reaction is depicted as follows:

Reaction Scheme B ##STR5## wherein R₄, R₅ and R₆ are as previouslydefined.

In those instances, wherein X is other than lower alkyl, hydroxy,alkoxy, halogen, nitro, cyano, amino, and R₃ is other than cyano, it ispreferred to prepare a compound of formula I wherein X is cyano, andthen, by the use of standard techniques, convert the cyano moiety to thedesired substituents. For example, the cyano moiety may be converted toa carboxyl moiety by hydrolyzing the nitrile with 6N hydrochloric acid,sulfuric and/or other mineral acids under standard conditions such as byheating at reflux temperatures for about 12-24 hours. The carboxylmoiety may be converted to an alkoxycarbonyl moiety by the standardFisher esterification procedure such as by heating thecarboxy-containing compounds with an appropriate alcohol in the presenceof an acid, e.g., 3% hydrochloric acid. The carboxamido-containingcompounds may be prepared by converting the alkoxycarbonyl moiety byheating the esters in the presence of ammonia or an appropriate amine,preferably in a pressure bomb at about 100°-150° C. in an inert solvent,e.g., benzene, toluene and the like. Alternatively, the carboxamidomoiety may be prepared by hydrolyzing a nitrile with concentratedsulfuric acid by heating on a steam bath at temperatures of about50°-100° C. In those instances wherein R₃ is cyano, it is preferred tohave the ultimately desired X substituent on the phenyl ring prior tothe Michael addition reaction between the 1-R₅ -3-R₆-2-(1-dimethyl-amino-1-R₄ -methylidenyl)-1,3-propanedione and the cyanosubstituted acetamide.

In those instances wherein X is imidazol-2-yl, such compounds areprepared by a condensation reaction wherein the nitrile is heated tofrom about 150°-200° C. with ethylene diamine for about 2 hours. Theamidino compounds are prepared from corresponding nitriles wherein thenitrile is converted to an imino ether which is converted to the amidinomoiety by treating the imino ether with ammonia in alcohol attemperatures of about 0° C. room temperature.

In those instances wherein the R₃ substituent is hydrogen, it ispreferred to chemically remove a cyano moiety from a compound of formulaI by standard techniques such as by conversion of the cyano moiety to acarboxyl radical by treatment with a strong acid and then the compoundis decarboxylated.

The preparation of the compounds of formula I may be illustrated by thefollowing specific examples.

PREPARATION OF INTERMEDIATE 1-R₅ -3R₆ -2-(1DIALKYLAMINO-1-R₄METHYLIDINYL)-1,3-PROPANDIONES Example 12-Dimethylaminomethylenyl-1-phenyl-1,3-butandione

A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamidedimethylacetal were stirred overnight at room temperature under argon.The resulting reddish-colored mixture was concentrated on the rotaryevaporator, then dissolved in THF (tetrahydrofuran). The resultingsolution was stirred and heated to boiling and slowly diluted withhexane. At the point of turbidity heating was discontinued. An orangegum precipitated and rapidly solidified. The mixture was chilled in anice bath and filtered yielding 25.25 g (78%) of2-(dimethyl-amino)-1-phenyl-1,3-butanedione m.pt. 72°-74° C.

In a similar manner, by substituting the 1,3-propanediones of theforegoing example with the appropriately substituted analogs thereof andby substantially following the procedures there is produced thefollowing intermediates:

1-(4-pyridyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(2-thienyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-[2-(1-H-pyrryl)]-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(3-furanyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-methoxyphenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-methylphenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-nitrophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-aminophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(2,4-dichlorophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-cyanophenyl)-2-[1-(dimethylamino)ethylidenyl]-1,3-butandione.

PREPARATION OF FINAL PRODUCTS Example 25-Acetyl-1,2-dihydro-2-oxo-6-phenyl-3-pyridinecarbonitrile

Cyanoacetamide (2.50 g, 0.03 mole) was added to a stirred suspension ofsodium hydride in (150 ml) THF and warmed to 50° C. The mixture wasallowed to cool to room temperature then3-[(dimethylamino)methylenyl]-1-phenyl-1,3-butanedione (6.52 g, 0.03mole) dissolved in THF (20 ml) was added all at once. The suspension washeated and stirred at 50° C. overnight. The reaction mixture was allowedto cool to room temperature, treated with acetic acid to pH 6 andconcentrated on the rotary evaporator. Workup as in Example 5 gave 3.0 gof a yellow powder. The powder was mixed with 10 g of silica gel (60-200mesh) and flash chromatographed eluting with 25% EtOAC -75% CH₂ Cl₂collecting 50 ml fractions to yield 1.1 g of5-acetyl-1,2-dihydro-2-oxo-6-phenyl-3-pyridinecarbonitrile m.pt.259°-261° C. in fractions 11 to 20.

Example 3 5-Benzoyl-1,2-Dihydro-6-Methyl-2-Oxo-3-pyridinecarbonitrile

The chromatography in Example 6 gave 1.1 g of5-benzoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile in fractions24 to 40 m.pt. 265°-261° C.

Example 4 3-Cyano-1,2-Dihydro-6-Methyl-2-Oxo-5-Pyridinecarboxylic acidethyl ester

Ethylacetoacetate (6.5 g, 0.050 mole) and dimethylformamide dimethylacetal (7.14g, 0.060 mole) were stirred together under argon overnight.The resulting reddish oil was concentrated on the rotary evaporator andthe concentrate then dissolved in THF (10 ml) and quickly added to asuspension of cyanoacetamide (4.20 g, 0.050 mole) and sodium hydride inTHF (175 ml). The reaction mixture was heated and stirred overnight at50° C. The reaction mixture was neutralized to pH 6 with acetic acid andconcentrated on the rotary evaporator. The residue was triturated with a50:50 CH₂ Cl₂ -H₂ O mixture collected and recrystallized (EtOAC) giving4.7 g of 3-cyano-1,2-dihydro-6-methyl-2-oxo-5-pyridinecarboxylic acidethyl ester m.pt. 208°-210° C.

Example 56-Ethyl-1,2-Dihydro-5-[(4-Methylthio)benzoyl]-2-Oxo-3-Pyridinecarbonitrileand5-(1-Oxopropyl)-1,2-Dihydro-6-(4-Methylthiophenyl)-2-Oxo-3-Pyridinecarbonitrile

1-[4-((methylthio)phenyl)]-1,3-pentanedione (2.66 g, 0.12 mole) anddimethylformamide dimethylacetal (1.79 g, 0.015 mole) were stirredovernight at room temperature. The resulting red oil was concentrated onthe rotary evaporator and the concentrate was dissolved in THF and addedto a suspension of cyanoacetamide (0.84 g, 0.010 mole) and sodiumhydride (0.25 g, 0.010 mole) in THF (50 ml), and, with constant stirringheated at 50° C. for 15 hours and cooled. The mixture was brought to pH6 with acetic acid and concentrated. The residue was dissolved in CH₂Cl₂, extracted with 5% NaHCO₃, washed with brine, separated, dried(MgSO₄) and filtered. Concentration on the rotary evaporator gave ayellow gum which upon trituration with Et₂ O solidified.Recrystallization (EtOAC) gave 1.37 g m.pt. 208°-210° C. The HPLC (uBondpack CN column, 55% MEOH/45% H₂ O) showed two peaks in roughly a40:60 ratio).

In a similar manner by utilizing the named intermediates of Example 1and by substantially following the teachings of Examples 2-5, there areproduced the following compounds.

5-(4-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile;

5-(2-thienoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile;

5-[2-(1H-pyrryoyl)]-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbontrile;

5-(3-furanoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile;

5-(2-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile;

5-(4-methoxybenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

5-(4-methylbenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

5-(4-nitrobenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

5-(4-aminobenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

5-(2,4-dichlorobenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

5-(4-methylthiobenzoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile;

and the 6-methyl homologs thereof.

The compounds of general Formula 1 may be used in the treatment ofcardiac failure including congestive heart failure, backward heartfailure, forward heart failure, left ventricular heart failure, or rightventricular heart failure or in the treatment of any other conditionwhich requires the strengthening of heart action with a cardiotonic.

The utility of Formula 1 compounds as cardiotonics may be determined byadministering the test compound (0.01-10 mg/kg) intravenously,intraperitoneally, intraduodenally or intragastrically in a suitablevehicle to a mongrel dog (either sex). The test dogs are anesthetizedand prepared by isolating a suitable artery (e.g., femoral or commoncarotid) and vein (e.g., femoral or external jugular) introducingpolyethylene catheters filled with 0.1% Heparin-Na to record arterialblood pressure and administer compounds, respectively. The chest isopened by splitting the sternum at the midline or by an incision at theleft fifth intercostal space, and a pericardial cradle is formed tosupport the heart. A Walton-Brodie strain gage is sutured to the rightor left ventricle to monitor myocardial contractile force. Anelectromagnetic flow probe may be placed around the root of theascending aorta for measuring cardiac output less coronary blood flow.Heart failure is induced by administering sodium pentobarbital (20 to 40mg/kg) followed by a continuous infusion of 1-2 mg/kg/min. orpropranalol hydrochloride (4 mg/kg) followed by a continuous infusion of0.18 mg/kg/min. to the blood perfusing the heart. Followingadministration of either of these cardiac depressants, the right atrialpressure dramatically increases and cardiac output is severelydepressed. Reversal of these effects by the test compound indicatescardiotonic activity.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eitherorally or parenterally, that is, intravenously or intramuscularly. Theamount of compound administered will vary with the patient, the severityof the cardiac failure and the mode of administration.

For oral or parenteral administration the cardiotonically effectiveamount of compound is from about 0.01 mg/kg of patients body weight perday up to about 500 mg/kg of patient body weight per day and preferablyfrom about 0.10 mg/kg of patient body weight per day up to about 200mg/kg of patient body weight per day.

For oral administration a unit dosage may contain, for example, from 1.0to 750 mg of the active ingredient, preferably about 10 to 250 mg of theactive ingredient. For parenteral administration a unit dosage maycontain, for example, from 5 to 500 mg of the active ingredient,preferably about 10 to 250. Repetitive daily administration of thecompounds may be desired and will vary with the condition of the patientand the mode of administration.

As used herein the term patient is taken to mean warm blooded animals,particularly mammals, such as humans.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment the compounds of general Formula 1 canbe tableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water, alcohols, oils and otheracceptable organic solvents with or without the addition of a surfactantand other pharmaceutically acceptable adjuvants. Illustrative of oilswhich can be employed in these preparations are those of petroleum,animal, vegetable, or synthetic origin, for example, peanut oil, soybeanoil and mineral oil. In general, water, saline, aqueous dextrose andrelated sugar solutions, ethanol and glycols such as propylene glycol orpolyethylene glycol or 2-pyrrolidone are preferred liquid carriers,particularly for injectable solutions.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, a siliconerubber manufactured by the Dow-Corning Corporation.

As is true in many large classes of compounds certain subgeneric membersand certain specific members of the class are preferred for thepharmaceutical activity in treating disease states in man. In thisinstance the preferred compounds of formula I are those wherein R₅ iseither phenyl or X-substituted phenyl and R₆ is methyl or ethyl. Thepreferred R₃ substituent is cyano or amino. The preferred R₄ substituentis hydrogen.

We claim:
 1. A compound of the formula: ##STR6## or a pharmaceuticallyacceptable salt thereof wherein R₃ is H or --CN,R₄ is hydrogen or loweralkyl, R₅ is pyridyl, and R₆ is hydrogen, methyl, or ethyl.
 2. A methodof treating cardiac failure in a patient in need thereof which comprisesadministering to said patient a cardiotonically effective amount of acompound of the formula: ##STR7## or a pharmaceutically acceptable slatthereof wherein R₃ is H or --CN,R₄ is hydrogen or lower alkyl, R₅ ispyridyl, and R₆ is hydrogen, methyl, or ethyl.
 3. A compound accordingto claim 1 wherein R₃ is --CN.
 4. A compound according to claim 1 whichis 5-(4-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile. 5.A compound according to claim 1 which is5-(2-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 6. Acompound according to claim 1 which is5-(4-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 7. Acompound according to claim 1 which is5-(2-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 8. Amethod of claim 2 wherein R₃ is --CN.
 9. A method of claim 8 which is5-(4-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 10. Amethod of claim 8 which is5-(2-pyridoyl)-6-ethyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 11. Amethod of claim 8 which is5-(4-pyridoyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.
 12. Amethod of claim 8 which is5-(2-pyridoyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridine-carbonitrile.